REVIEW

THOMAS F. KEYS, MD Department of Infectious Disease, Cleveland Clinic

Infective endocarditis: Prevention, diagnosis, treatment, referral

ABSTRACT Infective endocarditis is a challenge to the primary care physician, who is not likely to see more than several cases a year. With proper diagnosis and treatment, the overall cure rate is over 80% and major complications such as congestive heart failure can be avoided. In some patients, even in some with acute infection, surgical intervention to restore cardiac function significantly improves the outcome. Guidelines for prophylaxis before various surgical procedures are presented.

KEY POINTS Fever, regurgitant heart murmur, classic vascular skin lesions, and multiple positive blood cultures are virtually diagnostic.

Echocardiography can detect valve lesions associated with endocarditis and is used to follow up patients who have or develop valve dysfunction and may need surgery.

Nosocomial bacteremia and fungemia are newly appreciated risk factors for infective endocarditis.

Although antibiotic prophylaxis to prevent endocarditis remains unproven, it is accepted practice for patients at risk who are undergoing invasive procedures.

NFECTIVE ENDOCARDITIS is a chal lenge to busy primary care physicians or

internists. Infectious disease specialists see cases with some regularity and so are familiar with the syndrome and the intricacies of the diagnosis and treatment. But other clinicians are unlikely to encounter more than one or two cases a year.

This review outlines the cardinal manifes-tations of infective endocarditis, guidelines for diagnosis, empiric and specific treatment, indications for surgery, and an approach to prophylaxis.

• RISK FACTORS FOR INFECTIVE ENDOCARDITIS

In general, a history of infective endocarditis, prosthetic valvular heart disease, or regurgi-tant heart murmur greatly increases the risk for infective endocarditis (TABLE 1 ) .

Furthermore, 1% to 3 % of patients who undergo valvular heart surgery contract endo-

TABLE 1

Primary risk factors for infective endocarditis

History of infective endocarditis

Prosthetic valvular heart disease

Complex cyanotic heart disease

Surgically constructed pulmonary shunts

Acquired valvular heart disease

Hypertrophic cardiomyopathy

Mitral valve prolapse wi th regurgitation

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ENDOCARDITIS KEYS

FIGURE 1. Vascular skin lesions associated with infective endocarditis

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Look for lesions on the palms or soles, under the nail beds, in the subconjunctival sacs, or on the soft palate

Raised red nodule on palm Fine raised rash on palm and fingers (Pseudomonas aeruginosa) (Actinobacillus actinomycetemcomitans)

Embolic lesion on dorsum of foot (.Acinetobacter calcoaceticus)

"Flea-bitten" rash on toes (Enterococcus faecalis)

Petechial rash on soles (Viridans streptococci)

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carditis within 60 days after the operation. Fortunately, the incidence is much lower now than in the days before standardized surgical techniques and antibiotic prophylaxis.

Today, nosocomial bacteremia is a grow-ing conccrn in at-risk patients hospitalized for other medical and surgical problems. Sources of infection include surgical wounds, vascular catheters, and arteriovenous fistulae used for hemodialysis.1 Staphylococcus aureus, often methicillin-resistant, may lead to endocarditis in up to 25% of cases.

Intravenous drug addiction continues to be a risk factor for endocarditis. S aureus is the usual pathogen in these individuals, although gram-negative bacteria and fungi are also seen.

• D IAGNOSIS

Key clues The key clinical clues to the diagnosis of infective endocarditis are fever, regurgitant heart murmur, and vascular skin lesions.2 The skin lesions ( F I G U R E 1 ) are found especially on the palms or soles, under the nail beds ("splin-ter hemorrhages"), in the subconjunctival sacs, or on the soft palate.

Heart disease, weight loss, and spleno-megaly are additional clues but are less specif-ic since they are often associated with other disease processes.

C o n f i r m i n g t h e diagnosis When fever, a regurgitant hear murmur, vascu-lar skin lesions, weight loss, and splenomegaly are present in a patient who has risk factors for endocarditis, the clinician should consider the diagnosis and collect three blood cultures within 24 hours. Patients with sustained bac-teremia due to typical organisms are likely to have endocarditis.3 Transesophageal echocar-diography can confirm the diagnosis by show-ing cardiac lesions compatible with vegetation or abscess ( F I G U R E z)A

Negative blood cultures ("culture-nega-tive endocarditis") or cultures that produce an organism not usually associated with endo-carditis pose a diagnostic problem. Nevertheless, if the clinical picture suggests infective endocarditis and transesophageal echocardiography shows compatible lesions, the patient should be treated.

FIGURE 2. Transesophageal echocardiogram showing vegeta-tions on anterior leaflet (top arrow) and papillary muscle (bottom arrow) of mitral valve.

Pursuing 'cu l tu re -negat ive ' endocard i t is A frequent cause of culture-negative endo-carditis is suboptimal antibiotic therapy before the diagnosis is considered—eg, oral antibi-otics prescribed for vague fever. Even minute concentrations of antibiotic in the blood may inhibit culture growth, especially streptococci that may be exquisitely susceptible to the penicillins. Ideally, one should wait at least 24 hours after the last dose of antibiotic before collecting blood cultures. In some cases, if necessary, two or more blood cultures beyond the usual two or three sets should be obtained, spaced several days apart.

If these strategies fail, one should consider empiric therapy directed at the usual causes of endocarditis (eg, streptococci in patients with native heart valves, or staphylococci in patients with prosthetic heart valves). About 50% of patients will respond clinically to empiric therapy.

If a patient remains ill after 7 to 10 days of therapy, further diagnostic studies should be pursued. For example, the epidemiologic set-ting may suggest a diagnosis of Q-fever (due to Coxiella burnetii) or bartonellosis (due to Bartonella henselae).

Fungal endocarditis. At least 50% of patients with fungal endocarditis have nega-tive blood cultures. Consider it in patients who have undergone prolonged antibiotic therapy, parenteral nutrition through central

Multiple positive blood cultures for typical organisms clinch the diagnosis

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ENDOCARDITIS KEYS

T A B L E 2

Empiric antibiotic therapy for endocarditis in adults with normal renal function

C L I N I C A L S E T T I N G L I K E L Y P A T H O G E N S A N T I B I O T I C R E G I M E N *

Patient has native valve

Not acutely ill

Acutely ill

Intravenous drug abuser

Patient has prosthetic valve Onset w i th in 60 days

Onset after 60 days

Viridans streptococci HACEK organisms1

Staphylococcus aureus Streptococcus pneumoniae

Staphylococcus aureus Pseudomonas aeruginosa

Staphylococcus epidermidis Staphylococcus aureus

Viridans streptococci Staphylococcus epidermidis Staphylococcus aureus

Ampici l l in 2 g every 4 hours, plus Gentamicin 1.5 mg/kg every 12 hours

Vancomycin 1.0 g every 12 hours, plus Gentamicin 1.5 mg/kg every 12 hours

Vancomycin 1.0 g every 12 hours, plus Gentamicin 3.0 mg/kg every 12 hours

Vancomycin 1.0 g every 12 hours, plus Gentamicin 1.5 mg/kg every 12 hours

Ampici l l in ' 2 g every 4 hours, plus Vancomycin 1.0 g every 12 hours, plus Gentamicin 1.5 mg/kg every 12 hours

'All doses given intravenously tHaemophilus sp, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella sp •Vancomycin may be substituted for ampicillin in patients allergic to penicillin

MODIFIED FROM THE AMERICAN HEART ASSOCIATION AND INFECTIOUS DISEASE SOCIETY OF AMERICA RECOMMENDATIONS, REFERENCE 8

Start empiric intravenous antibiotics against the likely pathogen

TABLE 3

Antibiotic therapy for infective endocarditis due to streptococci and enterococci in adults with normal renal function

O R G A N I S M T Y P E A N T I B I O T I C R E G I M E N -

Penicillin-sensitive streptococcus (penicillin MIC+ < 0.1 pg/mL)

Penicillin G* 18 mil l ion units daily for 4 weeks, or Ceftr iaxone 2.0 g every 24 hours for 4 weeks

Penicillin-insensitive streptococcus Penicillin G* 18 mil l ion units daily for 4 weeks, plus (penicillin MIC > 0 .1 and < 0.5 pg/mL) Gentamicin 1.5 mg/kg every 12 hours for 2 weeks

Enterococcus species or streptococcus Penicillin G* 30 mil l ion units daily for 4 - 6 weeks, plus either (penicillin MIC > 0.5 pg/mL)

Vancomycin-resistant enterococcus (vancomycin MIC > 8 pg/mL)

Gentamicin 1.5 mg/kg every 12 hours for 4 - 6 weeks (if gentamicin MIC is < 500 pg/mL), or

Streptomycin 7.5 mg/kg every 12 hours for 4 - 6 weeks (if streptomycin MIC is < 2,000 |jg/mL)

Quinupristin-dalfopristin 7.5 mg/kg every 8 hours for 6 weeks

'All doses given intravenously •Minimal inhibitory concentration of the isolate to an antibiotic •Vancomycin 1.0 g intravenously every 12 hours can be substituted if the patient is allergic to penicillin

MODIFIED FROM THE AMERICAN HEART ASSOCIATION AND INFECTIOUS DISEASE SOCIETY OF AMERICA RECOMMENDATIONS, REFERENCE 8

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T A B L E 4 Antibiotic therapy for infective endocarditis due to staphylococci and HACEK group organisms in adults with normal renal function

S E T T I N G A N D P A T H O G E N A N T I B I O T I C R E G I M E N *

Patient w i t h native valve Methici l l in-susceptible Staphylococcus aureus or 5 epidermidis

Methici l l in-resistant 5 aureus or or 5 epidermidis

HACEK group organisms* Patient w i t h prosthetic valve

Methici l l in-susceptible 5 aureus or S epidermidis

Methici l l in-resistant 5 aureus or 5 epidermidis

HACEK group organisms*

Oxacill in* 2.0 g every 4 hours for 6 weeks

Vancomycin 1.0 g every 12 hours for 6 weeks

Ceftriaxone 2.0 g every 24 hours for 4 weeks

Oxacillin* 2.0 g every 4 hours for 6 weeks, plus Rifampin 300 mg by mouth every 8 hours for 6 weeks, plus Gentamicin 1.5 mg/kg every 12 hours for 2 weeks Vancomycin 1.0 g every 12 hours for 6 weeks, plus Rifampin 300 mg by mouth every 8 hours for 6 weeks, plus Gentamicin 1.5 mg/kg every 12 hours for 2 weeks

Ceftriaxone 2.0 g every 24 hours for 6 weeks

"All doses intravenously unless otherwise stated *Vancomycin 1.0 g intravenously every 12 hours may be substituted if the patient is allergic to penicillin *HACEK group includes Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomi-tans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae

MODIFIED FROM THE AMERICAN HEART ASSOCIATION AND INFECTIOUS DISEASE SOCIETY OF AMERICA RECOMMENDATIONS, REFERENCE 8

vascular catheters, or immunosuppressive therapy. Fungi such as Candida and Aspergillus can produce large valvular vegetations. Surgical intervention with debridement and valve replacement is usually required. The diagnosis may only be established by stains, smears, and cultures of resected valves or other embolic lesions found during surgery.

• M E D I C A L M A N A G E M E N T OF INFECTIVE E N D O C A R D I T I S

Before the advent of antibiotics, death was the near-universal outcome for patients with infective endocarditis. Today, with appropri-ate antibiotic and surgical therapy, the death rate is 15% to 20%.5

Empi r ic t h e r a p y Once a working diagnosis of infective endo-carditis is established, begin aggressive intra-venous antibiotic therapy directed at a likely pathogen ( T A B L E 2 ) .

T a r g e t i n g s t rep tococc i a n d en te rococc i Most patients with native valve or late-onset prosthetic valve endocarditis have infection due to streptococcal species. Therapy ( T A B L E S )

is guided by the minimal inhibitory concen-tration (MIC) of the isolate to penicillin. Patients with an isolate MIC equal to or less than 0.1 jlg/mL should receive intravenous penicillin or ceftriaxone alone for 4 weeks. Ceftriaxone is as effective as penicillin and more convenient for the stable patient, as it may be continued at home.6 Patients with an M I C from 0.1 to 0.5 |J.g/mL should receive intravenous penicillin with gentamicin for 6 weeks. Higher doses of penicillin are recom-mended when the MIC is greater than 0.5 (ig/mL, or the organism is an enterococus.

Vancomycin-resistant enterococci are a growing concern. One study7 reported suc-cess with quinupristin-dalfopristin plus doxycycline and rifampin, but at present, options are limited and treatment is often unsuccessful.

Anti-streptococcal therapy is guided by the MIC

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ENDOCARDITIS KEYS

Prosthetic valve endocarditis needs more aggressive treatment than native valve endocarditis

Algorithm for the diagnosis and management of infective endocarditis

Suspect infective endocarditis if patient has fever, heart murmur, classic vascular skin lesions, weight loss, splenomegaly

I Check for key risk factors: history of endocarditis, presence of prosthetic heart valve, invasive procedures such as dental extractions, nosocomial bacteremia or fungemia, intravenous drug abuse

Clinical picture compatible with infective endocarditis? I

YES

I Discontinue antibiotic therapy, then collect two or three blood cultures

Cultures positive for bacteria typically associated with infective endocarditis (streptococci, staphylococci, HACEK organisms)?

YES

I Start antibiotic therapy, adjusting for susceptibility Monitor closely for signs of congestive heart failure, valve dysfunction, persistent fever, conduction defects, major embolic events

I If valve dysfunction or abscess is found, refer for surgical debridement or valve repair or replacement

NO Pursue other diagnoses

NO • Refer for transesophageal echocardiography and/or serologic studies

H M YES Positive results

NO

I Pursue other diagnoses

FIGURE 3

T a r g e t i n g s taphy lococc i T A B L E 4 lists recommended therapies for staphy-lococci and the HACEK group of fastidious gram-negative bacteria8 (Haemophilus sp, Actinobacillus actinomycetemcomitans, Cardio-bacterium hominis, Eikenella corrodens, Kingella sp). Note that therapy for prosthetic valve endocarditis must be more intensive and pro-longed because relapse and failure rates are higher than in patients with native valve endocarditis, F IGURE 3 provides an algorithm for the overall management of infective endo-carditis.

H TERTIARY CARE REFERRAL A N D SURGICAL M A N A G E M E N T

G u i d e l i n e s f o r r e f e r r a l While most patients with infective endocardi-tis respond to antibiotic therapy and have a smooth course with a favorable outcome, some require more intensive evaluation and treatment beyond antibiotics. For example, in patients with congestive heart failure, the heart failure may or may not be associated with valvular or cardiac dysfunction due to endocarditis, and serial transesophageal

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• T A B L E 5

Antibiotic prophylaxis for invasive procedures

PROCEDURE PROPHYLACTIC REGIMEN

Oral, respiratory, esophageal Dental extraction Periodontal procedures Dental implants Prophylactic cleaning Tonsillectomy, adenoidectomy Rigid bronchoscopy Esophageal dilation Sclerotherapy

Gastrointestinal, genitourinary Endoscopic retrograde cholangiopancreatography for biliary obstruction

Biliary tract surgery Operations on intestinal mucosa Prostate surgery Cystoscopy Urethral dilation

Amoxici l l in* 2 g by mouth 1 hour before the procedure, or 2 g intramuscularly or intravenously 1/2 hour before the procedure

Ampici l l in* 2 g intramuscularly or intravenously, plus Gentamicin 1.5 mg/kg intramuscularly or intravenously 1/2 hour before the procedure

"Substitute clindamycin 600 mg by mouth or intravenously if patient is allergic to penicillin ADAPTED FROM THE AMERICAN HEART ASSOCIATION RECOMMENDATIONS,REFERENCE 11

echocardiographic studies are needed to assess valve function during medical therapy. Such patients are best managed at a tertiary medical center with expertise in cardiology and car-diothoracic surgery, where special technology and appropriate surgery are readily available.

Surgica l i n t e r v e n t i o n Surgical intervention must be available immediately when medical management fails. In the past, surgeons were reluctant to operate on patients with active infection, but we know now that restoration of cardiac function by surgery clearly improves outcome. The per-sistence of fever beyond several days of thera-py or the development and evolution of first-degree atrioventricular block on the electro-cardiogram might indicate an annular or myocardial abscess, which will also likely require surgery.9 Even after antibiotic therapy has been completed, patients are at risk for mechanical valve dysfunction, and a signifi-cant number require corrective surgery some-time in the near future.

N e u r o l o g i c c o m p l i c a t i o n s of e n d o c a r d i t i s While major neurologic complications from endocarditis are rare, they are associated with significant morbidity and mortality. This is especially true when the organism is S aureus. Embolic strokes and encephalopa-thy are usually seen during the initial pre-sentation of the illness. Brain abscesses and mycotic aneurysms are more worrisome but, fortunately, are even rarer. Mycot ic aneurysms in the cerebral circulation are usually peripheral and small and resolve with antibiotic treatment. Aneurysms that are more central may bleed into the sub-arachnoid space or ventricles, and neurosur-gical intervention is usually required. Large brain abscesses may need to be drained sur-gically.

In general, anticoagulation therapy should be discontinued because of the increased risk of intracranial bleeding from such neurologic complications. However, this decision depends on the type of valve, cardiac rhythm, and prior valve-related embolic events.

Surgery restores cardiac function and improves outcome

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ENDOCARDITIS KEYS

We have little evidence that antibiotic prophylaxis really works

• PROPHYLAXIS GUIDELINES FOR INFECTIVE ENDOCARDITIS

The n e e d for an t ib io t ic prophylaxis Although antibiotic prophylaxis to prevent endocarditis has become standard practice before a number of surgical and dental proce-dures, there is little published evidence to sug-gest that it really works. A controversial case-control study10 of dental and cardiac risk fac-tors in 273 patients concluded that dental treatment does not seem to increase the risk for infective endocarditis and that "few cases of infective endocarditis would be preventable with antibiotic prophylaxis, even with 100% effectiveness assumed," and it called for a reconsideration of current prophylaxis poli-cies.10 However, the study did confirm that cardiac valvular abnormalities are clearly asso-ciated with risk for endocarditis. These abnor-malities include mitral valve prolapse, con-genital heart disease, rheumatic valvular heart disease, previous cardiac surgery, and a history of infective endocarditis. A known cardiac murmur was associated with a sixfold increase in risk.

Guidelines for prophylaxis have been recently updated by the American Heart Association.11 Diseases associated with risk for endocarditis are listed in TABLE 1, and prophy-lactic regimens for dental and other invasive procedures are described in TABLE 5.

Patients who undergo cardiac valve surgery should receive perioperative antibiotic prophylaxis with a first-generation or second-generation cephalosporin. For surgical centers with a high prevalence of methicillin-resistant staphylococci, vancomycin should be used instead. The antibiotic infusion must be given

shortly before the skin incision, preferably within 30 minutes. The antibiotic should not be continued longer than 24 hours after the operation. Some surgeons give a preoperative dose and another dose during surgery if the operation is longer than 4 hours, and no more is given afterward. 13

• REFERENCES 1. Fowler VG, Sanders LL, Kong LK et al. Infective endo-

carditis due to Staphylococcus aureus. Clin Infect Dis 1994; 28:106-114.

2. Von Reyn CF, Levy BS, Arbeit RD, et al. Infective endo-carditis: an analysis based on strict case definitions. Ann Intern Med 1981; 94:505-518.

3. Werner AS, Cobbs CG, Kaye D, et al. Studies on the bac-teremia of bacterial endocarditis. JAMA 1967; 202:127-131.

4. Durack DT, Lukes AS, Bright KD, et al. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographicfindings. Am J Med 1994; 96:200-209.

5. Bayliss R, Clarke C, Oakley, et al. Incidence, mortality, and prevention of infective endocarditis. J Royal Coll Phys London 1986; 20:15-20.

6. Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once daily for 4 weeks compared with ceftriaxone plus gentamicin once daily for 2 weeks for treatment of endo-carditis due to penicillin-susceptible streptococci. Clin Infect Dis 1998; 27 1470-1474.

7. Matsumura S, Simor AE. Treatment of endocarditis due to vancomycin-resistant Enterococcus faecium with quin-upristin/dalfopristin, doxycycline, and rifampin. Clin Infect Dis 1998; 27:1554-1556.

8. Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA 1995; 274:1706-1713.

9. Douglas A, Moore-Gillon J, Eykyn S. Fever during treat-ment of infective endocarditis. Lancet 1986; 1:1341-1343.

10. Strom BL, Abrutyn E, Berlin JA, et al. Dental and cardiac risk factors for infective endocarditis. Ann Intern Med 1998; 129:761-769.

11. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997; 277:1794-1801.

ADDRESS: Thomas F. Keys, MD, Department of Infectious Disease, Cleveland Clinic Foundation, 9500 Euclid Avenue, S32, Cleveland, Ohio 44195-5066, e-mail keyst@ccf.org.

• CLEVELAND CLINIC CENTER FOR CONTINUING EDUCATION

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